Human neural stem cell and endothelial cell reciprocal interactions govern cell function

Project Summary Neural stem/progenitor cells (NSPCs) lie in close proximity to blood vessels in brain stem cell niches and after transplant to treat neurological conditions. This adjacency allows for considerable interaction between NSPCs and the endothelial cells (ECs) that form blood vessels, creating an interdependent and complex relationship between these cell types. Human NSPC (hNSPC) and human EC (hEC) interactions have not been well studied, creating knowledge gaps that hinder our understanding of human brain function and repair after injury. We used a tissue engineering approach with a a 3D scaffold mimicking brain properties to study hNSPC-hEC interactions. We found hEC contact with hNSPCs induced the formation of GFAP+/ SOX2+ cells, which could be type B adult neural stem cells. Type B cells are slowly dividing NSPCs that prevent depletion of the NSPC pool and may be activated after injury to help replace lost brain cells. We found hNSPCs stimulate hEC vessel formation (vasculogenesis) and this effect is mediated by hNSPC secreted components rather than hNSPC contact with hECs. These data lead to the hypothesis that hEC contact promotes a type B adult neural stem cell phenotype while hNSPC secreted components stimulate human vessel formation in 3D niches. We will test this hypothesis with the following Aims: Aim 1 - determine how contact with hECs affects hNSPCs; Aim 2 - determine how hNSPC secreted components impact human vessels; Aim 3 - test whether hNSPCs and hECs promote type B adult neural stem cells and vessels in vivo. By investigating the crucial interactions between hNSPCs and hECs in 3D tissue engineered niches, we will better understand how their relationship impacts human brain function. This knowledge could be used in the future to optimize co-transplants of hNSPCs and hECs in scaffolds to recreate critical niche interactions leading to formation of type B cells and vessels that stimulate brain repair.